Resistance to insecticides is a critical problem in the control of insect vectors of human disease. It causes the failure of a major method of disease control, and this results in the reemergence of diseases affected areas. In order to prevent, or delay, the development of insecticide resistance in disease vectors, an understanding of its underlying biological mechanisms must be attained. This understanding will improve the management of vector programs and the durability of an important method of disease control. The long term goal of this research is to develop such an understanding using a model insect, Tribolium castaneum. This insect has long been associated with insecticide resistance, and is an excellent experimental organism for studies of genetics, and molecular and population biology. Thus, molecular genetic studies of Tribolium ar an appropriate approach for gaining an understanding of the mechanisms that cause insecticide resistance at the molecular, cellular, organismic and population levels. As a major step toward the long term goal, the proposed research uses molecular genetics to understand the metabolic resistance associated with cytochromes P450 enzymes. Specifically, the genes that encode these enzymes will be investigated in Tribolium so that their numbers and distribution in all insects can be estimated. The expression of these genes in susceptible and resistant beetles will be compared in an effort to identify the specific P450 genes that confer resistance. In addition, other genes which modify the resistance associated with P450 enzymes will be identified and isolated into separate strains so that their interactions can be evaluated and understood in future experiments.